Pancreatic Ductal Adenocarcinoma (PDA) is the most frequent pancreatic cancer and the fourth cause of cancer death in the United States and Europe. Most patients die within 12 months, and only 2% survive five years after diagnosis. Pancreatectomy remains the cornerstone of PDA management and chemotherapy but provides marginal survival benefit (Laheru D and Jaffee M, 2005; Kleef J et al., 2006).
Despite improved surgical and medical management (including the use of monoclonal antibodies, vaccines, and chemotherapy), there are still few and poorly reliable markers for early PDA diagnosis. The most widely used serological marker for pancreatic cancer diagnosis is sialylated Lewis blood group antigen CA 19-9, but its use is mostly directed toward monitoring response to therapy, rather than PDA diagnosis. In fact, this antigen may also be present at elevated concentrations in the sera from patients affected by benign pancreatic diseases (such as chronic pancreatitis or biliary obstruction) providing false positives, and it cannot be used in all cases because it is not expressed at all in 5-10% of the population (Okusaka T et al., 2006).
It is for these reasons that alternative biomarkers arc under evaluation for use in PDA diagnosis, with the aim to limit invasive procedures such as biopsies and histopathological evaluation (Bouvet M, 2004; Brand R, 2001; Goggins M, 2005; Leung T et al., 2005), and for evaluating drug candidates (Cohen S and Meropol N, 2002; Jimeno A and Hidalgo M, 2006).
Various technologies have been recently employed for the identification of candidate PDA biomarkers using large scale analysis of protein expression (either based on RNA or protein levels). In particular, proteomic technologies have been used to detect antigens that elicit a humoral response in the sera of PDA patients by comparing the proteins that are resolved by two-dimensional gel electrophoresis (2-DE), recognized by serum antibodies from cancer patients, and identified using Mass Spectrometry (Gorg A et al., 2004; Graham D et al., 2005). Variants of this approach for protein separation, selection and characterization have been described under different names in the literature, such as SERPA (Klade C et al., 2001), PROTEOMEX (Lichtenfels R et al., 2003), or SPEAR (Unwin R et al., 2003).
The work hypothesis common to these methodologies is that, by characterizing the B cell repertoire against antigens specifically expressed by cancers (the so-called human cancer immunome), it should be possible to define specific targets that are involved in cancer immunosurveillance and immunoediting, and to understand the mechanisms leading to uncontrolled cell proliferation and metastasis (Drake C et al., 2006; Dunn G et al., 2004).
It has been suggested that immunotherapy can be a valuable approach for the treatment of pancreatic cancer (Laheru D and Jaffee M, 2005). In fact, lists of candidate PDA-specific proteins have been generated on the basis of their elevated expression at the RNA level (WO 04/55519), or of large-scale proteomic analysis of serum samples and/or pancreatic samples (Bhattacharyya S et al., 2004; Cao D et al., 2005; Ceeconi D et al., 2003; Chen R et al., 2005; Gronborg M et al., 2006; Honda K et al., 2005; Koomen J et al., 2005; Rodriguez J et al., 2005; Shen J et al., 2004, Rosty C and Goggins M, 2005; Sinha P et al., 1999; Yu Y et al., 2005). Candidate proteins for PDA diagnosis in sera are Fibrinogen gamma (Bloomston M et al., 2006), DEAD-Box protein 48 (Xia Q et al., 2005), MIC-1 (Koopmann et J al., 2004), PTH-related protein (Bouvet M et al., 2001), and calreticulin (Hong S et al., 2004).
However, reliable biomarkcrs for the carly detection of PDA and its differentiation from other pancreatic pathologies or cancers are still needed.